Use of dietary fibres against muscle wasting

ABSTRACT

A composition nutritional containing dietary fibres is useful for the treatment of muscle wasting, if the dietary fibre comprise at least 30 wt. % of galacto-oligosaccharides or other oligosaccharides having mainly anhydropyranose units, and having a chain length of 3-10 units. The composition may further contain other oligo- or polysaccharides, especially polysaccharides having a majority of anhydrofuranose units.

This application is a U.S. national stage application of InternationalApplication No. PCT/NL2006/050320, filed Dec. 18, 2006, which claimsforeign priority from EP Application No. 05112336.2, filed Dec. 16,2005, each of the above-identified applications is incorporated hereinby reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to the use of a nutritional orpharmaceutical composition comprising non-digestible oligosaccharidesfor the treatment or reduction of the incidence of muscle wasting.

BACKGROUND OF THE INVENTION

Severe weight loss and in particular muscle wasting is a seriousphenomenon that occurs on a broad scale in patients suffering fromdiseases, disorders and trauma. Muscle wasting (abbreviated as MW) inchronic disease is defined as an involuntary loss of body weight of morethan 5% within one month. If loss of lean body mass (abbreviated as LBM)occurs at a more gradual rate but during a longer period, the inventorsrefer to chronic muscle wasting (abbreviated as CMW), in particular ifmore than 10% of body weight is lost in a period of 6 months. MW istypically observed during recovery of trauma or surgery. CMW istypically observed in severe diseases such as cancer, AIDS, COPD,diabetes mellitus and heart failure. The rate of muscle wasting isassociated with increased morbidity and mortality. The cause of musclewasting as a result of a disease is thought to be multifactorial. Musclewasting can also be caused by malnourishment, in particularprotein-energy malnourishment. In particular the latter type ofmalnourishment can be treated or prevented by providing extra protein orenergy as proposed in EP 0721742.

Sarcopenia (abbreviated as SP) is the involuntary decline in lean musclemass, strength and function, which occurs with ageing. SP increases therisk of loss of functional capacity in the elderly, which is notnecessarily related to disease.

Dietary fibres are frequently used to initiate weight loss. Dietaryfibre lowers postprandial glucose levels in blood and has a satiatingeffect. Therefore, administration of substantial amounts of dietaryfibre is not normally recommended in cases of malnutrition, weight lossand muscle wasting. Dietary fibre has also been included in clinicalnutrition for influencing colonic flora and specific fibres or mixturesthereof have been claimed to decrease rate of systemic infections, e.g.in WO 02/26242, increase specific immune-related parameters, e.g. inEP-B 1105002, or decrease growth rate of selected tumours in animals,e.g. in Taper H., J. Nutr., 129 (1999), 1488-1491.

Many types of dietary fibre have been used in the manufacture ofnutritional products. Several of them strongly increase viscosity,others have a bad solubility or produce a sand-like feeling when presentin the mouth. Thus, there is a need for nutritional products, which canbe readily consumed by persons suffering from muscle wasting or chronicmuscle wasting, and which combat or prevent muscle wasting withouthaving the disadvantages of prior art products, such as a high viscosityof liquid drinks.

WO 2004/026294 discloses the use of a mixture of free essential aminoacids including leucine for improving the effects of tumour-inducedweight loss. The mixture can be combined with further components such asintact protein, ω-3 fatty acids and soluble fibre such as hydrolysedguar gum.

U.S. Pat. No. 6,387,883 teaches treatment of cachexia and anorexia byadministration of ω-3 fatty acids, branched-chain amino acids, andfurther components possibly including dietary fibre.

U.S. 2005/153019 is concerned with stimulating body protein synthesis byproviding a composition containing whey protein, ω-3 fatty acids,carbohydrates, vitamins, etc. The composition may further containprebiotic fibre, such as fructo-oligosaccharides, for promoting growthof bifidobacteria, but such compositions are not further illustrated.

U.S. Pat. No. 5,444,054 teaches a method of improving nutritional statusin case of ulcerative colitis or colic inflammation, using a combinationof the ω-3 fatty acids EPA and DHA, and indigestible carbohydrates, suchas gum Arabic and fructo- and xylo-oligosaccharides.

DESCRIPTION OF THE INVENTION

It was surprisingly found that a dietary fibre comprising at least 30wt. % of non-digestible oligosaccharides and a nutritional orpharmaceutical product containing such fibre fulfill this need. This isin contrast to the prior art, which frequently uses fibres to initiateweight loss. The non-digestible soluble oligosaccharides to be usedaccording to the invention have a chain length of 3-10 anhydromonoseunits.

In a preferred embodiment, the anhydromonose units of the non-digestibleoligo-saccharides have a majority of anhydropyranose units. Theseanhydropyranose units have a six-membered ring structure and comprisethe anhydro forms of aldoses such as galactose, mannose, xylose, as wellas their deoxy forms (such as fucose and rhamnose), their acid formssuch as galacturonates and glucuronates, and their amino forms andN-acylamino forms (such as galactosamine), as well as their higherhomologues (such as neuraminic acid and other sialic acids). They mayalso comprise anhydroglucose units and their derivatives, as long as theoligosaccharides remain essentially indigestible. Therefore, theoligosaccharides do not contain more than 2 or preferably less than twoα-1,4-linked anhydroglucose units. Also, a minority of otheranhydromonose units, e.g. anhydroarabinose units, (whether in pyranosideor furanoside form), may be present in the oligosaccharides. Theanhydromonose units may be connected to each other by α- or β-linkagesbetween the first (anomeric) carbon atom of one anhydromonose with the2^(nd), 3^(rd), 4^(th) (or 6^(th) in the case of hexoses) carbon atom ofthe neighbouring anhydromonose moiety by means of an oxygen atom, as hasbeen described in the art for many indigestible carbohydrates.

The preferred oligosaccharides of this embodiment are galacto-, manno-and/or xylo-oligosaccharides. They can be homo-oligosaccharides orhetero-oligosaccharides containing galactose, mannose and/or xyloseunits, which may further contain 10 to 35% anhydroglucose and/oranhydro-arabinose units, anhydrofucose, anhydroglycosamine and/orN-acetyl-anhydroglycosamine units, preferably in a terminal position.Though hetero-oligomers are effective, it is sometimes preferred from acost-effective point of view to include homologous variants of thepyranose oligosaccharides. In this context oligosaccharides having onlya single different monosaccharide unit at their terminal position, suchas a glucose unit in galacto-oligosaccharides, are still considered tobe homo-oligomers.

In another embodiment, the anhydromonose units of the non-digestibleoligo-saccharides have a majority of anhydrofuranose units. Theseanhydrofuranose units have a five-membered ring structure and comprisethe anhydro forms of aldoses or ketoses such as fructose or arabinose,as well as their deoxy forms, their amino forms and N-acylamino forms,as well as their higher homologues. They may also compriseanhydroglucose units and their derivatives, as long as theoligosaccharides remain essentially indigestible. Therefore, theseoligosaccharides do not contain more than 2 or preferably less than twoα-1,4-linked anhydroglucose units. Also, a minority of otheranhydromonose units, whether in pyranoside or furanoside form, may bepresent in these oligosaccharides.

In a further, preferred embodiment of the invention, theoligosaccharides are composed of two classes, one having a majority ofanhydropyranose units and one having a majority of anhydrofuranoseunits, each as defined above. In this embodiment, the dietary fibrecontains at least 40 wt. %, preferably at least 50 wt. %, morepreferably at least 60 wt. % of total non-digestible oligosaccharides,including 30-98 wt. %, preferably 50-96 wt. %, of oligosaccharides ofthe first class (pyranose-based) and 2-50 wt. %, preferably 4-30 wt. %of oligosaccharides of the second class (furanose-based). These weightpercentages are based on the weight of the fibre composition. The weightratio between the first class and the second class is preferably between98:2 and 2:98, more preferably between 97:3 and 10:90, most preferablybetween 96:4 and 50:50.

The oligosaccharides to be used according to the invention can beobtained by methods well-known in the art. According to a first method,suitable polysaccharides can be hydrolysed selectively or at random bychemical (acid) or, preferably enzymatic, hydrolysis. For example guargum, locust bean gum, carob or tara galactomannans can be subjected to atreatment with P-mannanase and/or α-galactosidase at pH 3-6 to produce alow-viscosity product, especially when part or all of the galactose isremoved from the polymer through the action of α-galactosidase. Asanother example, galactans and arabinogalactans can be hydrolysed by theappropriate (endo-β-1,3-)galactans, optionally in combination witharabinosidases to remove the arabinose side chains, and xylans andarabinoxylans can be hydrolysed using (β-)xylanases, optionally togetherwith arabinosidases and/or galacturonidases. By choosing the appropriatehydrolysis conditions, low-viscosity oligosaccharides having therequired chain length can be obtained. In general,hetero-oligosaccharides such as galactosyl-oligomannans,arabinosyl-oligogalactans and arabinosyl-oligoxylans can be obtainedupon endoglycolytic hydrolysis wherein the side chain is not removed,and largely homo-oligosaccharides can be obtained upon enzymatic removalof the side chains. In the case of hydrolysates of galactomannans suchas guar gum, the amount of mannobiose, mannotriose andgalacto-manno-oligo-saccharides is preferably more than 20%, preferably40-100% of the oligosaccharides. As a further example, insulin can beused as such, or after chemical or enzymatic hydrolysis; such hydrolysisresults in oligofructoses having a terminal glucose unit, and pureoligo-fructoses.

According to a second general method, (hetero)oligosaccharides can bemanu-factured by enzymatic transglycosylation of suitable substrateswith one or more suitable enzymes or one or more micro organisms oryeasts equipped with these enzymes. Examples of suitable substrates aresolutions of the mono- or di-hexoses, lactose or fibres or partialhydrolysates thereof, such as hydrolysates of guar gum.

In particular galacto-oligosaccharides (GOS) are very suitable formanufacturing effective nutritional or pharmaceutical compositions.Suitable galacto-oligosaccharides are commercially available and includeoligosaccharides manufactured from lactose by means of a reaction withβ-galactosidase. Preferably, these galacto-oligosaccharides comprise atleast 67%, especially at least 80% by weight of oligosaccharides havinga chain length of 3 up to 5 units, disregarding mono- and disaccharidessuch as lactose.

Effective doses of the soluble dietary fibre compositions are 0.1-20,preferably 0.6-10, more preferably 0.8-5 gram per dose for a personweighing 80 kg. For persons (including infants) having a different bodyweight the dose is proportionally lower. In terms of dosage per kg bodyweight, the preferred daily dosages are between 1.2 and 250 mg,preferably 7.5-130, more preferably 10-65 mg per kg per day.

Other parts of the soluble fibre fraction can includenon-oligosaccharides, like soluble and fermentable and non-fermentablefibres, including polysaccharides from the furanose type. Examples areinsulin, other fructo-polysaccharides (fructans), moderately hydrolysedpectin and other gums, like glucomannans (e.g. Konjae), galactomannans(e.g. guar), xanthan, and Arabic gum. These polysaccharides (having achain length (DP) of more than 10 units) can be included up to 70 wt. %of the soluble fibre composition. However, it is preferred that thefibre composition contains at least 50%, more preferably at least 70%,up to e.g. 95 or even 98% or 100% of the oligosaccharides, especiallythe (galacto-, manno-, xylo-)oligosaccharides as defined above. Theremainder may be con-stituted by one or more of the solublepolysaccharide fibres, especially of the fructan type. In addition tothe soluble fibre fraction, non-soluble fibres can be incorporated in afibre blend, like resistant starch, and non-soluble fermentable andnon-fermentable fibres, such as cellulose. It is preferred that thenon-soluble fibres represent less than 50 wt. % of the soluble fibrefraction, in particular between 5 and 25 wt. % thereof.

In specific embodiments, the soluble fibre composition may contain 2-50wt. %, in particular 5-30 wt. % of fructans (DP≧3) and/or 2-35 wt. %, inparticular 5-25 wt. % of other soluble polysaccharides, such ashydrolysed galactomannan (having more than 10 anhydromonose units).

Other components that beneficially can be included in the compositionsare specific proteins, lipids, carbohydrates, and micro ingredients.

The compositions can be liquid, semi-solid or solid. In liquid solution,the inclusion of the oligosaccharides according to the invention resultsin non-viscous products, having a viscosity below 70, preferably 1-40,more preferably 2-30 MPa·s at 100 sec⁻¹ shear rate and 20° C., whenincluded in effective amounts, which makes the solutions suitable foruse as a tube feeding. In liquids the effective dose will be included ina serving size. For tube feeding this is assumed to be 2000 ml per day,given in two portions per day. When the liquid product is used as asupplement, e.g. in portions of 200 ml, the concentration can becalculated accordingly. Typically the concentration of effectiveoligosaccharides will be well below 15, e.g. 0.05-10, preferably 0.5-9,more preferably 1-8% weight/volume. When the product has a semi-solidform such as a pudding, or a solid form such as a bar, the product willbe used as a supplement and has a serving size of 25-200 ml. Theconcentration will therefore be 0.1-20 g per 25-200 g product. On anenergy basis, the content of the soluble fibre composition is preferably0.5-10 g per 419 KJ (100 kcal), more preferably 1-4 g per 419 KJ (100kcal).

The energy content of liquid compositions will typically be in the rangeof 2.5-16.8, preferably 5.0-16.8, more preferably 5.4-8.4, and mostpreferably 6.3-8.0 KJ/ml (0.6-4.0, preferably 1.2-4.0, more preferably1.3-2.0 and most preferably 1.5-1.9 kcal/ml).

It is preferred that a nutritional composition according to theinvention contains at least a protein fraction. The weight ratio betweenthe fibre fraction and the protein fraction being preferably between5:95 and 75:25, more preferably between 10:90 and 50:50.

The protein fraction should preferably comprise more than 45, preferably48-70, more preferably 52-65 wt. % essential amino acids, based on totalamino acids. Essential amino acids are methionine, leucine, isoleucine,valine, phenylalanine, tryptophan, histidine, lysine and threonine. Theamount of essential amino acids in liquid products will typically bemore than 4.75 g, preferably 4.9-9.0, more preferably 5.1-7 g per 100ml.

In particular it is preferred that the amount of leucine+isoleucine ismore than 18.0 wt. %, based on the total sum of amino acids, and morepreferably 18.5-25 wt. %. The amount of leucine is preferably more than11.0, more preferably more than 11.4 wt. %, most preferably 12.2-20 wt.%. The amount of branched chain amino acids will typically be more than2.9, preferably 3.0-4.0, more preferably 3.0-3.4 g per 100 ml liquidproduct.

The energy contribution of the protein fraction is preferably 25-75,more preferably 26-60, most preferably 26-50 en % of the nutritionalcomposition. The energy contribution of the intact protein fraction ispreferably 17-40, more preferably 19-30, most preferably 20-29 en % ofthe nutritional composition. The protein fraction should preferablycontain more than 10%, more preferably 20-60% of intact whey protein orpeptide fragments thereof.

The lipid fraction should comprise long chain fatty acids of the omega-3type. Long-chain means at least 18 C atoms. Particularly preferred arefatty acids having 20-26 carbon atoms and having 4 or more unsaturatedbonds. The amount of the sum of long-chain polyunsaturated fatty acidsshould be more than 10 wt. % of the sum of all fatty acids, preferably15-50, more preferably 17-42, in particular 18-42 wt. %. The weightratio between ω-3 long-chain polyunsaturated fatty acids (LCP's), suchas α-linoleic, stearidonic, timnodonic (EPA), clupanodonic (DPA),cervonic (DHA) and nisinic acid (THA), and the soluble fibre ispreferably between 90:10 and 5:95, more preferably between 80:20 and15:85. The combination of the long-chain polyunsaturated fatty acids andthe soluble fibre and optional further components, can suitably be usedas a food supplement. It is preferred that the soluble fibre comprisesgalacto-, manno- and/or xylo-oligosaccharides, especiallygalacto-oligosaccharides, at a level of e.g. at least 50% w/w of thesoluble fibre. The energy contribution of the lipid fraction ispreferably 15-45, more preferably 20-35 en % of the nutritionalcomposition.

The carbohydrate fraction can comprise glucose, maltodextrins, starchand/or other sugars. In a preferred embodiment, the carbohydratefraction comprises 5-50 wt. % ribose, especially 8-25 wt. % of ribose inorder to prevent muscle wasting. On the basis of the soluble fibrecomposition, ribose is preferably present in a weight ratio of between9:1 and 1:9, more preferably 4:1 to 1:4. This combination can be used asa food supplement. It is preferred that such a supplement also comprisesother digestible carbohydrates, in an amount of 1-19 parts per part ofribose. In a the nutritional composition also containing lipids and/orproteins, the energy contribution of the digestible carbohydratefraction is preferably 15-55, more preferably 25-50 en % of composition.

It is further preferred that the carbohydrate fraction compriseslactose. If present the amount of lactose is more than 2, morepreferably 3-40, most preferably 10-30 wt. % of the digestiblecarbohydrate fraction. A useful carbohydrate composition can contain3-40 wt. %, preferably 5-30 wt. %, of the soluble fibre composition asdescribed above, and 3-40 wt. %, preferably 5-30 wt. %, of ribose and/or5-40 wt. %, preferably 8-30 wt. % of lactose, and preferably 20-80 wt.%, more preferably 35-70 wt. % of other digestible carbohydrates.

Contrary to prior art knowledge it is important to include an availablecarbohydrate fraction which has a low glycemic index for achieving adecrease in the rate of muscle wasting or even an increase in bodyweight. The available carbohydrate fraction is defined to possess a lowglycemic index (GI) its value is less than 70% of the value of glucose.The carbohydrate fraction should preferably contain more than 20% ofthese carbo-hydrates, more preferably 40-80 wt. %. Low GI sugars includelactose, trehalose, isomalto-oligosaccharides (oligosaccharides having apredominant portion of α-1,6 glucose units).

It is also preferred to include a low amount of sweet sugars in order toincrease food consumption of diseased persons. The amount of sugarshaving a sweetness less than 70% of that of sucrose should be more than20 wt. % of the available carbohydrate fraction. In particular theamount is 25-60 wt. %. Low-sweetness sugars include palatinose(isomaltulose), maltodextrins DE 2-47, galactose, mannose, lactose andtrehalose. Alternatively, the total proportion of low GI and/orlow-sweetness sugars, selected from galactose, mannose, otherglucose-containing disaccharides than sucrose and maltose (includinglactose, trehalose and palatinose), and isomalto-oligosaccharides, isthus preferably 20-80 wt. %, more preferably 25-60%.

All minerals and micro ingredients that are required for proper feedingof human beings are typically included. Typically per daily dose0.5-1.5× the recommended daily amounts are included, with the exceptionof folates, which are included in 1-4 times the recommended dailyamounts (especially 300-1200 μg/day or 50-1000 μg, especially 60-600 μgper g soluble fibre).

EXAMPLE 1 Material & Methods

Male CD2F1 mice (BALB/c×DBA/2, Harlan, the Netherlands) were used andthe C-26 adenocarcinoma cells were used to induce cachexia in thetumour-bearing groups (TB), whereas the control mice (C) received a shaminjection. The food consisted of 51% galacto-oligosaccharides (GOS) andfructo-polysaccharides (9:1), 19% maltodextrin, 16% lactose and 14%glucose in experiment 1. In experiment 2, the FOS was replaced byadditional GOS. GOS spray-dried powder of trans-galacto-oligosaccharideshaving a degree of polymerisation (dp) 3-8 (Vivinal GOS, Borculo Domo,Zwolle, NL) and FOS had a high degree of polymerisation (Raftiline HP,Orafti, Wijchen, NL; average dp>23). Following inoculation of tumourcells, tumour mass and skeletal muscles (extensor digitorum longus (EDL)and soleus muscles) were dissected and weighed.

Experiment 1

Control mice = C Tumour-bearing mice = TB Tumour-bearing + GOS/FOS =TB-Gos Fos

Experiment 2

Control mice = C Tumour-bearing mice = TB Tumour-bearing + GOS = TB-GosResults

The table below represents the muscular mass (mg, +% loss to C) ofexperiments 1 and 2.

m. EDL m. Soleus Experiment 1 C 9.5 ± 0.8 * 6.5 ± 0.6 * TB 7.7 ± 0.6(−19.0%) 5.5 ± 0.7 (−15.4%) TB-Gos Fos 8.2 ± 0.6 (−13.7%) * 5.8 ± 0.9(−10.6%) Reduction in mass loss 28% 30% by Gos/Fos Experiment 2 C 9.8 ±0.8 * 7.5 ± 0.7 * TB 7.7 ± 0.6 (−21.4%) 5.6 ± 0.4 (−25.3%) TB-Gos 8.2 ±0.6 (−16.3%) * 6.2 ± 0.6 (−17.3%) * Reduction in mass loss 26% 32% byGos/FosFrom the present data is concluded that galacto-oligosaccharides areresponsible for the attenuation of the muscular loss in cancer cachexia.The asterisks (*) show statistical difference (P<0.025) with TB group.

EXAMPLE 2

A liquid formula was prepared for patients that suffer from chronicmuscle wasting. It contains per 100 ml

Energy 658 kJ (157 kcal) Protein [8.2 g casein and whey, 1.8 g Leu] 10.0g Lipids [marine oil, vegetable] 5.3 g a. EPA 0.56 g b. DHA 0.27 gCarbohydrates 17.4 g a. sucrose 4.21 g b. maltodextrin 8.42 g c.trehalose 4.21 g d. lactose 0.59 g Fibre 2.05 g a. inulin DP > 20 0.1 gb. hydrolysed inulin DP < 20 0.08 g c. GOS 1.53 g d. resistant starch0.05 g e. cellulose 0.31 g

EXAMPLE 3

A liquid formula was prepared for patients suffering from chronic musclewasting. The formula contains per 100 ml:

Energy 662 kJ (158 kcal) Protein [casein, whey + 1 g Leu, 0.5 g Met, 0.5g Arg] 10.0 g Lipids [marine oil, vegetable] 5.3 g Carbohydrates[saccharide blend] 17.5 g Fibre [GOS + polyfructose 9:1] 2.1 g Ash 1.2 g

EXAMPLE 4

A liquid formula was prepared for patients suffering from chronic musclewasting. The formula contains per 100 ml:

Energy 587 kJ (140 kcal) Protein [casein + 0.9 g Leu, 0.5 g Ile, 0.2 gVal] 9 g Lipids 5.0 g Carbohydrates (10 wt. % free ribose) 15 g Fibre[hydrolysed guar + GOS ratio 3:7] 1.5 g Minerals/trace elements/vitaminsincluding 60 μg 2.0 g folate

EXAMPLE 5

A liquid formula for patients suffering from chronic muscle wastingcontains per 100 ml:

Protein [casein 6.1 + whey 2.9 + free Leu 1.1] 10.1 g Lipids [EPA 0.6,DHA 0.29, ω-3/ω-6 = 1.16, 5.6 g PUFA's 2.5; MUFA 1.5; saturated 0.76]Digestible carbohydrates [sucrose 3.92, lactose 0.7 16.4 g maltodextrins7.84; trehalose 3.92] Fibre [hydrolysed inulin DP < 20 0.2 + GOS 1.8]2.0 g Minerals/trace elements/vitamins

1. A method for the treatment of muscle wasting and/or chronic musclewasting and/or sarcopenia in a patient suffering from cancer, comprisingadministering to the patient a composition comprising a dietary fibre,wherein the dietary fibre comprises at least 30 wt. % oligosaccharideshaving a chain length of 3-10 anhydromonose units.
 2. The methodaccording to claim 1, wherein the nutritional composition furthercomprises oligosaccharides having a chain length of 3-10 anhydromonoseunits, whererin a majority of the anhydromonose units is selected fromthe group of mannose, xylose, their deoxy forms, amino forms andN-acylamino forms.
 3. The method according to claim 1, wherein thedietary fibre comprises 30-96 wt. % galacto-oligosaccharides having achain length of 3-10 anhydromonose units, and 4-50 wt. % ofoligosaccharides and/or polysaccharides in which the anhydromonose unitshave a majority of anhydrofructose units.
 4. The method according toclaim 1, wherein the dietary fibre comprises 50 to 100 wt. % of theoligosaccharides having a chain length of 3-10 anhydromonose units. 5.The method according to claim 4, wherein the dietary fibre comprises 70to 98 wt. % of the oligosaccharides having a chain length of 3-10anhydromonose units.
 6. The method according to claim 1, wherein thecancer is a tumour of the liver, pancreas, lungs, skin, oesophagus,brain, head or neck.
 7. The method according to claim 1, wherein thenutritional composition further comprises digestible carbohydrates,fats, proteins, or a combination thereof.
 8. The method according toclaim 7, wherein the nutritional composition is a liquid compositionhaving a viscosity of less than 35 Mpa.s at a shear rate of 100 sec⁻¹ at20° C.
 9. The method according to claim 7, wherein the nutritionalcomposition has an energy density between 5.0 and 16.8 kJ/ml (1.2 and4.0 kcal/ml).
 10. The method according to claim 7, wherein thenutritional composition has an energy density between 5.4 and 8.4 KJ/ml(1.3 and 2.0 kcal/ml).
 11. The method according to claim 1, wherein thecomposition further comprises a component supporting nucleotidesynthesis and/or folate metabolism.
 12. The method according to claim11, wherein the component supporting nucleotide synthesis and/or folatemetabolism is folate in an amount of 50-1000 μg per g of fibrecomposition.
 13. The method according to claim 1, wherein thecomposition further comprises a carbohydrate fraction having a glycemicindex of less than 70% the glycemic index of glucose.